Glucocorticoid- and pioglitazone-induced proteinuria reduction in experimental NS both correlate with glomerular ECM modulation
Sagar Bhayana,
Julie A. Dougherty,
Yu Kamigaki,
Shipra Agrawal,
Saranga Wijeratne,
James Fitch,
Amanda P. Waller,
Katelyn J. Wolfgang,
Peter White,
Bryce A. Kerlin,
William E. Smoyer
Affiliations
Sagar Bhayana
Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
Julie A. Dougherty
Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
Yu Kamigaki
Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
Shipra Agrawal
Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
Saranga Wijeratne
Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
James Fitch
Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
Amanda P. Waller
Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
Katelyn J. Wolfgang
Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
Peter White
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA; Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
Bryce A. Kerlin
Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
William E. Smoyer
Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA; Corresponding author
Summary: Idiopathic nephrotic syndrome (NS) is a common glomerular disease. Although glucocorticoids (GC) are the primary treatment, the PPARγ agonist pioglitazone (Pio) also reduces proteinuria in patients with NS and directly protects podocytes from injury. Because both drugs reduce proteinuria, we hypothesized these effects result from overlapping transcriptional patterns. Systems biology approaches compared glomerular transcriptomes from rats with PAN-induced NS treated with GC vs. Pio and identified 29 commonly regulated genes-of-interest, primarily involved in extracellular matrix (ECM) remodeling. Correlation with clinical idiopathic NS patient datasets confirmed glomerular ECM dysregulation as a potential mechanism of injury. Cellular deconvolution in silico revealed GC- and Pio-induced amelioration of altered genes primarily within podocytes and mesangial cells. While validation studies are indicated, these analyses identified molecular pathways involved in the early stages of NS (prior to scarring), suggesting that targeting glomerular ECM dysregulation may enable a future non-immunosuppressive approach for proteinuria reduction in idiopathic NS.
